Inhibition of miR-188-5p alleviates hepatic fibrosis by significantly reducing the activation and proliferation of HSCs through PTEN/PI3K/AKT pathway.
Inhibition of miR-188-5p alleviates hepatic fibrosis by significantly reducing the activation and proliferation of HSCs through PTEN/PI3K/AKT pathway.
复制标题
抑制 miR-188-5p 通过 PTEN/PI3K/AKT 通路显着减少 HSC 的活化和增殖，从而减轻肝纤维化
DOI：
10.1111/jcmm.16376
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发表时间：
2021-04
影响因子：
5.3
通讯作者：
Li D
中科院分区：
文献类型：
--
作者：
Riaz F;Chen Q;Lu K;Osoro EK;Wu L;Feng L;Zhao R;Yang L;Zhou Y;He Y;Zhu L;Du X;Sadiq M;Yang X;Li D
持续性肝损伤和肝脏慢性炎症可激活静止的肝星状细胞（hepatic stellate cells，HSC），导致肝纤维化（hepatic fibrosis，HF）。几种microRNA调节HSC的活化和增殖，从而在HF进展中发挥关键作用。先前的研究已经报道了miR-188 - 5 p在HF过程中失调。然而，miR-188 - 5 p在HF中的作用仍不清楚。本研究探讨了miR-188 - 5 p在HSC和HF中的潜在作用。首先，我们验证了从四氯化碳（CCl 4）诱导的小鼠肝脏、TGF-β1诱导的LX-2细胞、6个月高脂饮食（HFD）诱导的大鼠和4个月HFD诱导的小鼠NASH模型的肝脏以及人类非酒精性脂肪性肝病（NAFLD）患者中分离的原代细胞中的miR-188 - 5 p表达。此外，我们使用miR-188 - 5 p抑制剂来研究miR-188 - 5 p抑制在HFD + CCl 4诱导的体内模型中的治疗效果以及miR-188 - 5 p在HSC活化和增殖中的潜在作用。本研究报告了miR-188 - 5 p在人NAFLD、从CCl 4诱导小鼠肝脏分离的HSC以及体外和体内HF模型中的表达显著增加。模拟miR-188 - 5 p通过直接靶向磷酸酶和张力蛋白同源物（PTEN）导致HSC活化和增殖的上调。此外，抑制miR-188 - 5 p可通过PTEN/AKT途径降低HSC的活化和增殖标志物。此外，体内抑制miR-188 - 5 p可抑制HF参数、促纤维化和促炎基因以及纤维化。总的来说，我们的结果揭示了miR-188 - 5 p的促纤维化作用。此外，我们证明了miR-188 - 5 p抑制通过PTEN/AKT途径减少HSC的活化和增殖来降低HF的严重程度。
Persistent hepatic damage and chronic inflammation in liver activate the quiescent hepatic stellate cells (HSCs) and cause hepatic fibrosis (HF). Several microRNAs regulate the activation and proliferation of HSCs, thereby playing a critical role in HF progression. Previous studies have reported that miR‐188‐5p is dysregulated during the process of HF. However, the role of miR‐188‐5p in HF remains unclear. This study investigated the potential role of miR‐188‐5p in HSCs and HF. Firstly, we validated the miR‐188‐5p expression in primary cells isolated from liver of carbon tetrachloride (CCl4)‐induced mice, TGF‐β1‐induced LX‐2 cells, livers from 6‐month high‐fat diet (HFD)‐induced rat and 4‐month HFD‐induced mice NASH models, and human non‐alcoholic fatty liver disease (NAFLD) patients. Furthermore, we used miR‐188‐5p inhibitors to investigate the therapeutic effects of miR‐188‐5p inhibition in the HFD + CCl4 induced in vivo model and the potential role of miR‐188‐5p in the activation and proliferation of HSCs. This present study reported that miR‐188‐5p expression is significantly increased in the human NAFLD, HSCs isolated from liver of CCl4 induced mice, and in vitro and in vivo models of HF. Mimicking the miR‐188‐5p resulted in the up‐regulation of HSC activation and proliferation by directly targeting the phosphatase and tensin homolog (PTEN). Moreover, inhibition of miR‐188‐5p reduced the activation and proliferation markers of HSCs through PTEN/AKT pathway. Additionally, in vivo inhibition of miR‐188‐5p suppressed the HF parameters, pro‐fibrotic and pro‐inflammatory genes, and fibrosis. Collectively, our results uncover the pro‐fibrotic role of miR‐188‐5p. Furthermore, we demonstrated that miR‐188‐5p inhibition decreases the severity of HF by reducing the activation and proliferation of HSCs through PTEN/AKT pathway.
影响因子：
2.7
作者：
Yi S;Qin X;Luo X;Zhang Y;Liu Z;Zhu L
通讯作者：
Zhu L